The objectives of the proposed research are to define the anticonvulsant properties of marihuana and surrogates, particularly delta 9-tetrahydrocannabinol delta 9-THC) and 11-OH-delta 9-THC, to evaluate the potential of cannabinoids as antiepileptic drugs, to determine if marihuana produces a "rebound" CNS hyperexcitability which may increase seizure susceptibility in epileptic patients, to assess whether marihuana can potentially jeopardize the effectiveness of antiepileptic drugs, and to study the metabolism and fate of delta 9- THC in the body. The anticonvulsant activity and the effect on excitability and seizure susceptibility will be studied in rats and mice by a variety of electroshock and pentylenetetrazol tests. Minimum neurotoxicity will be estimated with the use of a rotating rod test. The results of these studies will provide comparative data with clinically useful antiepileptic drugs and will serve to establish delta 9-THC as a standard of reference for the evaluation of the clinical potential of other anticonvulsant cannabinoids. The drug interaction aspect will be investigated by determining whether marihuana alters the anticonvulsant activity of diphenylhydantoin, phenobarbital, ethosuximide, and trimethadione. The influence of the drug in these studies will be evaluated following both single doses and chronic administration in order to simulate the situations encountered in marihuana users. The metabolism and the fate will be studied with H3-delta 9-THC and thin layer chromatography. The purpose of these experiments is to identify the active substance or substances by correlating plasma, CSF, and brain levels with anticonvulsant activity. The influence of chronic treatment with delta 9-THC on its anticonvulsant activity and metabolism, and on the concentration of the parent substance and its metabolic products in the brain will also be investigated.